tbuckley/cabot-search huggingface dataset:
Single-cell transcriptome profiling of the immune space-time landscape reveals dendritic cell regulatory program in polymicrobial sepsis
Authors: Ren-qi Yao, Zhi-xuan Li, Li-xue Wang, Yu-xuan Li, Li-yu Zheng, Ning Dong, Yao Wu, Zhao-fan Xia, Timothy R. Billiar, Chao Ren, Yong-ming Yao
Journal: Theranostics (2022)

Rationale: Evident immunosuppression has been commonly seen among septic patients, and it is demonstrated to be a major driver of morbidity.Nevertheless, a comprehensive view of the host immune response to sepsis is lacking as the majority of studies on immunosuppression have focused on a specific type of immune cells.Methods: We applied multi-compartment, single-cell RNA sequencing (scRNA-seq) to dissect heterogeneity within immune cell subsets during sepsis progression on cecal ligation and puncture (CLP) mouse model.Flow cytometry and multiplex immunofluorescence tissue staining were adopted to identify the presence of 'mature DCs enriched in immunoregulatory molecules' (mregDC) upon septic challenge.To explore the function of mregDC, sorted mregDC were co-cultured with naïve CD4 + T cells.Intracellular signaling pathways that drove mregDC program were determined by integrating scRNA-seq and bulk-seq data, combined with inhibitory experiments.Results: ScRNA-seq analysis revealed that sepsis induction was associated with substantial alterations and heterogeneity of canonical immune cell types, including T, B, natural killer (NK), and myeloid cells, across three immune-relevant tissue sites.We found a unique subcluster of conventional dendritic cells (cDCs) that was characterized by specific expression of maturation-and migration-related genes, along with upregulation of immunoregulatory molecules, corresponding to the previously described 'mregDCs' in cancer.Flow cytometry and in stiu immunofluorescence staining confirmed the presence of sepsis-induced mregDC at protein level.Functional experiments showed that sepsis-induced mregDCs potently activated naive CD4 + T cells, while promoted CD4 + T cell conversion to regulatory T cells.Further observations indicated that the mregDC program was initiated via TNFRSF-NF-κB-and IFNGR2-JAK-STAT3-dependent pathways within 24 h of septic challenge.Additionally, we confirmed the detection of mregDC in human sepsis using publicly available data from a recently published single-cell study of COVID-19 patients.Conclusions: Our study generates a comprehensive single-cell immune landscape for polymicrobial sepsis, in which we identify the significant alterations and heterogeneity in immune cell subsets that take place during sepsis.Moreover, we find a conserved and potentially targetable immunoregulatory program within DCs that associates with hyperinflammation and organ dysfunction early following sepsis induction.
Engineering viral genomics and nano-liposomes in microfluidic platforms for patient-specific analysis of SARS-CoV-2 variants
Authors: Sandro Satta, Fahimeh Shahabipour, Wei Gao, Steven R. Lentz, Stanley Perlman, Nureddin Ashammakhi, Tzung Hsiai
Journal: Theranostics (2022)

New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are continuing to spread globally, contributing to the persistence of the COVID-19 pandemic.Increasing resources have been focused on developing vaccines and therapeutics that target the Spike glycoprotein of SARS-CoV-2.Recent advances in microfluidics have the potential to recapitulate viral infection in the organ-specific platforms, known as organ-on-a-chip (OoC), in which binding of SARS-CoV-2 Spike protein to the angiotensin-converting enzyme 2 (ACE2) of the host cells occurs.As the COVID-19 pandemic lingers, there remains an unmet need to screen emerging mutations, to predict viral transmissibility and pathogenicity, and to assess the strength of neutralizing antibodies following vaccination or reinfection.Conventional detection of SARS-CoV-2 variants relies on two-dimensional (2-D) cell culture methods, whereas simulating the micro-environment requires three-dimensional (3-D) systems.To this end, analyzing SARS-CoV-2-mediated pathogenicity via microfluidic platforms minimizes the experimental cost, duration, and optimization needed for animal studies, and obviates the ethical concerns associated with the use of primates.In this context, this review highlights the state-of-the-art strategy to engineer the nano-liposomes that can be conjugated with SARS-CoV-2 Spike mutations or genomic sequences in the microfluidic platforms; thereby, allowing for screening the rising SARS-CoV-2 variants and predicting COVID-19-associated coagulation.Furthermore, introducing viral genomics to the patient-specific blood accelerates the discovery of therapeutic targets in the face of evolving viral variants, including B1.1.7 (Alpha), B.1.351(Beta), B.1.617.2 (Delta), c.37 (Lambda), and B.1.1.529(Omicron).Thus, engineering nano-liposomes to encapsulate SARS-CoV-2 viral genomic sequences enables rapid detection of SARS-CoV-2 variants in the long COVID-19 era.
P2X2 receptors in pyramidal neurons are critical for regulating vulnerability to chronic stress
Authors: Xiao-Jing Kuang, Can-Yuan Zhang, Bing-Yi Yan, Wei-Zhong Cai, Cheng-Lin Lu, Li-Jia Xie, Shu-Ji Li, Peng-Li Kong, Jun Fan, Shu-Min Pan, Ting Guo, Xiong Cao
Journal: Theranostics (2022)

Rationale: Stress is a major risk factor for the development of depression.However, the underlying molecular mechanisms of stress vulnerability in depression are largely uncharacterized.Methods: P2X2 receptors (a major receptor for gliotransmitter-ATP) in the medial prefrontal cortex (mPFC) were identified by real-time qPCR, western blots and RNAscope in situ hybridization in chronic social defeat stress model (CSDS).We generated P2X2 conditional knockout mice and overexpressed AAV-P2X2 in CamkIIα-Cre mice.The depression-like behaviors were assessed via CSDS, subthreshold social defeat stress (SSDS), social interaction test (SI), forced interaction test (FIT), forced swimming test (FST), sucrose preference test (SPT), novel stressed feeding (NSF) and open field test (OFT).The neuronal activity and synapse function of P2X2 receptors in the mPFC were detected by in vivo fiber-photometry, patch-clamp techniques and neuronal morphometric analysis.Results: We identified that P2X2 receptors were increased in the mPFC of susceptible mice in CSDS.Conditional knockout of P2X2 receptors in pyramidal neurons promoted resilience of chronic stress-induced depressive-like behaviors, whereas pyramidal neurons -specific gain of P2X2 in the mPFC increased vulnerability to depressive-like behaviors.In vivo fiber-photometry, electrophysiology and neuronal morphometric analysis showed P2X2 receptors regulated neuronal activity and synapse function in the mPFC.Conclusions: Overall, our studies reveal a critical role of P2X2 in mediating vulnerability to chronic stress and identify P2X2 as a potential therapeutic target for treatment of stress-related mood disorders.
CLP36 promotes p53 deficient sarcoma progression through suppression of atrophin-1 interacting protein-4 (AIP-4)-dependent degradation of YAP1
Authors: Yixuan Lu, Yongxin Mu, Ju Chen, Xinyuan Guan, Ling Guo, Chuanyue Wu
Journal: Theranostics (2022)

Background: p53 deficiency is a key causal factor for tumor development and progression.p53 acts in this process through, at least in part, cooperation with YAP1 but the underlying molecular mechanism is incompletely understood.In this paper, we show that CLP36, an actinin-binding cytoskeletal protein, links p53 deficiency to up-regulation of YAP1 expression and sarcoma progression.Methods: Immunohistochemical staining and Western blotting were used to investigate the effect of p53 deficiency on CLP36 expression in sarcoma tissues and cells.Furthermore, molecular, cellular, and genetic knockout and knockdown approaches were employed to investigate the functions of CLP36 in regulation of sarcoma cell behavior in culture and tumor growth in mice.Finally, biochemical approaches were used to investigate the molecular mechanism by which CLP36 regulates the malignant behavior of p53 deficient sarcoma cells.Results: We have found that the expression of CLP36 is up-regulated in response to loss of p53 in sarcoma tissues and cells.Depletion of CLP36 inhibited malignant behavior of p53 deficient sarcoma cells.Furthermore, knockout of CLP36 in mice markedly inhibited p53 deficiency-induced tumorigenesis and improved the survival of the p53 deficient mice.Mechanistically, CLP36 promoted p53 deficiency-induced tumorigenesis through inhibition of E3 ligase atrophin-1 interacting protein-4 (AIP-4)-dependent proteasomal degradation of YAP1 and consequently increase of YAP1 expression.Conclusions: Our results reveal a crucial role of CLP36 in linking p53 deficiency to up-regulation of YAP1 expression and sarcoma progression.Our findings suggest that therapeutic targeting the CLP36/YAP1 signaling axis may provide an effective strategy for alleviation of p53 deficient sarcoma progression.
Interleukin-37 exacerbates experimental colitis in an intestinal microbiome-dependent fashion
Authors: Junxiao Cong, Dandan Wu, Hanying Dai, Yanmei Ma, Chenghui Liao, Lingyun Li, Liang Ye, Zhong Huang
Journal: Theranostics (2022)

Background: Inflammatory bowel disease (IBD) involves complicated crosstalk between host immunity and the gut microbiome, whereas the mechanics of how they govern intestinal inflammation remain poorly understood. In this study, we investigated the contribution of environmental factors to shaping gut microbiota composition in colitis mice that were transgenic for human IL-37, a natural anti-inflammatory cytokine possessing pathogenic and protective functions related to microbiota alterations. Methods: Mice transgenic expressing human IL-37 (IL-37tg) were housed under conventional and specific pathogen-free (SPF) conditions to develop a mouse model of dextran sulfate sodium (DSS)-induced colitis. 16S ribosomal RNA sequencing was used for analyzing fecal microbial communities. The efficacy of microbiota in the development of colitis in IL-37tg mice was investigated after antibiotic treatment and fecal microbiota transplantation (FMT). The mechanism by which IL-37 worsened colitis was studied by evaluating intestinal epithelial barrier function, immune cell infiltration, the expression of diverse cytokines and chemokines, as well as activated signaling pathways. Results: We found that IL-37 overexpression aggravated DSS-induced colitis in conventional mice but protected against colitis in SPF mice. These conflicting results from IL-37tg colitis mice are ascribed to a dysbiosis of the gut microbiota in which detrimental bacteria increased in IL-37tg conventional mice. We further identified that the outcome of IL-37-caused colon inflammation is strongly related to intestinal epithelial barrier impairment caused by pathogenic bacteria, neutrophils, and NK cells recruitment in colon lamina propria and mesenteric lymph node to enhance inflammatory responses in IL-37tg conventional mice. Conclusions: The immunoregulatory properties of IL-37 are detrimental in the face of dysbiosis of the intestinal microbiota, which contributes to exacerbated IBD occurrences that are uncontrollable by the immune system, suggesting that depleting gut pathogenic bacteria or maintaining intestinal microbial and immune homeostasis could be a promising therapeutic strategy for IBD.
NIR-II responsive PEGylated nickel nanoclusters for photothermal enhanced chemodynamic synergistic oncotherapy
Authors: Yong Qian, Jiahui Zhang, Jinglu Zou, Xingyu Wang, Xiangfu Meng, Hongji Liu, Yefeng Lin, Qianwang Chen, Lei Sun, Wenchu Lin, Hui Wang
Journal: Theranostics (2022)

Rationale: All kinds of non-metal and metal-based nanozymes have been extensively explored as Fenton agents for Chemodynamic therapy (CDT).However, the low catalytic efficiency of non-metallic nanozymes and the susceptibility to oxidation and long-term toxicity of metallo-nanozymes limit their potential in CDT.Methods: In this study, we report a magneto-solvothermal method to tune the crystallinity and shape of polyethylene glycol (PEG)-ylated urchin-like nickel nanoclusters (named as 9T-PUNNC) at a high magnetic field with an intensity of 9 T for enhanced combined photothermal-chemodynamic therapy. Results:The needle-like protrusions on the surface of 9T-PUNNC can effectively increase the reception of NIR light in second NIR window (NIR-II) and transform it into local hyperthermia, achieving effective photothermal treatment.The light and heat generated by NIR-II further promotes the release of Ni 2+ and improves the ability of Ni 2+ -mediated chemodynamic therapy (CDT).In addition, the surface coating of PEG on the surface of 9T-PUNNC improves its stability and biocompatibility of nanocrystals.In vitro and in vivo results indicate that the 9T-PUNNC could efficiently kill tumor cells (nearly 12 times more than control group) and inhibit tumor growth (nearly 9 times smaller than control group) under NIR-II irradiation through the synergistic effect of combined treatments.Conclusions: we developed a novel synthetic strategy to tune crystallinity and shape of PUNNC for enhanced NIR-II responsive photothermal conversion efficiency and accelerated acid-induced dissolution for improved •OH generation.Such 9T-PUNNC enable a combined chemodynamic-photothermal treatment to provide superior therapeutic efficacy due to their highly synergistic effect.
Progress in advanced nanotherapeutics for enhanced photodynamic immunotherapy of tumor
Authors: Xiao Wei, Mingzhu Song, Guirong Jiang, Min Liang, Chunlan Chen, Zhiyong Yang, Liang Zou
Journal: Theranostics (2022)

Clinically, the conventional treatments of cancer are still often accompanied by tumor recurrence, metastasis and other poor prognosis.Nowadays, more attention has been paid to photodynamic therapy (PDT), which is regarded as an adjuvant antineoplastic strategy with superiorities in great spatiotemporal selectivity and minimal invasiveness.In addition to eliminating tumor cells via reactive oxygen species (ROS), more meaningfully, this phototherapy can trigger immunogenic cell death (ICD) that plays a vital role in photodynamic immunotherapy (PDIT).ICD-based PDIT holds some immunotherapeutic potential due to further enhanced antitumor efficacy by utilizing various combined therapies to increase ICD levels.To help the PDIT-related drugs improve pharmacokinetic properties, bioavailability and system toxicity, multifunctional nanocarriers can be reasonably designed for enhanced PDIT.In further consideration of severe hypoxia, low immunity and immune checkpoints in tumor microenvironment (TME), advanced nanotherapeutics-mediated PDIT has been extensively studied for boosting antitumor immunity by oxygen-augment, ICD-boosting, adjuvant stimulation and combined checkpoints blockade.Herein, this review will summarize different categories of nanocarriers consisting of their material type, targeting and stimuli-responsiveness.Moreover, we will focus on the latest progress of various strategies to enhance the antitumor immune effect for PDIT and elucidate their corresponding immune-activation mechanisms.Nevertheless, there are several thorny challenges in PDIT, including limited light penetration, tumor hypoxia, immune escape and the development of novel small-molecule compounds that replace immune checkpoint inhibitors (ICIs) for easy integration into nanosystems.It is hoped that these issues raised will be helpful to the preclinical study of nanotherapeutics-based PDIT, thus accelerating the transformation of PDIT to clinical practice.
Continuous centrifugal microfluidics (CCM) isolates heterogeneous circulating tumor cells via full automation
Authors: Hyeong Jung Woo, Seung-Hoon Kim, Hyo Jung Kang, Soo-Hwan Lee, Seung Joon Lee, Jong Man Kim, Ogan Gurel, Soo Yeol Kim, Hye Ran Roh, Jungmin Lee, Yeonsoo Park, Hyun Young Shin, Yong-Il Shin, Sun Min Lee, So Yeon Oh, Young Zoon Kim, Jung-Il Chae, Seoyoung Lee, Min Hee Hong, Byoung Chul Cho, Eun Sook Lee, Klaus Pantel, Hye Ryun Kim, Minseok S. Kim
Journal: Theranostics (2022)

Understanding cancer heterogeneity is essential to finding diverse genetic mutations in metastatic cancers.Thus, it is critical to isolate all types of CTCs to identify accurate cancer information from patients.Moreover, full automation robustly capturing the full spectrum of CTCs is an urgent need for CTC diagnosis to be routine clinical practice.Methods: Here we report the full capture of heterogeneous CTC populations using fully automated, negative depletion-based continuous centrifugal microfluidics (CCM).Results: The CCM system demonstrated high performance (recovery rates exceeding 90% and WBC depletion rate of 99.9%) across a wide range of phenotypes (EpCAM(+), EpCAM(-), small-, large-sized, and cluster) and cancers (lung, breast, and bladder).Applied in 30 lung adenocarcinoma patients harboring epidermal growth factor receptor (EGFR) mutations, the system isolated diverse phenotypes of CTCs in marker expression and size, implying the importance of unbiased isolation.Genetic analyses of intra-patient samples comparing cell-free DNA with CCM-isolated CTCs yielded perfect concordance, and CTC enumeration using our technique was correlated with clinical progression as well as response to EGFR inhibitors.Conclusion: Our system also introduces technical advances which assure rapid, reliable, and reproducible results, thus enabling a more comprehensive application of robust CTC analysis in clinical practice.
Extracellular vesicles derived from astrocyte-treated with haFGF<sub>14-154</sub> attenuate Alzheimer phenotype in AD mice
Authors: Dong Peng, Youjin Wang, Yuanjie Xiao, Mengyuan Peng, Wanwen Mai, Bo Hu, Yanbin Jia, Hongxia Chen, Yan Yang, Qi Xiang, Zhijian Su, Qihao Zhang, Yadong Huang
Journal: Theranostics (2022)

Background: aFGF content in serum and cerebrospinal fluid is increased in Alzheimer's disease (AD) patients and attenuates the activation of astrocytes.Extracellular vesicles (EVs) are a major mediator in astrocyte-neuron communications.Since excessive or persistent reactive astrocytes lead to chronic inflammation and neuronal dysfunction, and the activation of astrocytes can be inhibited by aFGF, we proposed that the cargoes of astrocyte-derived EVs (AEVs) might be modified by aFGF stimulation, playing an important role in AD progression.However, the mechanisms underlying the role of aFGF remain unclear.Methods: AEVs were isolated from damaged astrocytes, treated with or without aFGF in Aβ-loading condition, and were intranasally administered to AD mice.We determined the ability of AEVs to enter the brain, ameliorate cognitive behavior deficits, alleviate the Aβ burden in the brain, and improve synapse ultrastructure.Subsequently, the miRNAs enriched in AEVs were sequenced to identify the key molecules specifically modified by aFGF.Finally, we explored the protective effects of miR-206-3p inhibition on cognitive deficiency and its regulatory mechanism and determined its role as a specific biomarker for potential AD diagnosis.Results: AEVs stimulated by aFGF (defined as AEVs-A β+H ) had favorable neuroprotection in AD pathology by enhancing neurite growth and reduction of Aβ loading on neurons in vitro.Following intranasal administration, AEVs-A β+H ameliorated cognitive behavior deficits, promoted synaptic plasticity, and alleviated brain Aβ burden in the APP/PS1 and Aβ brain-injected mice.AEVs-A β+H showed beneficial effects on AD similar to AEVs produced in normal situations (AEVs-Ctrl).aFGF stimulation modified the cargoes in EVs derived from Aβ damaged astrocytes, the most significant of which being the down-regulation of miR-206-3p.The miR-206-3p level was specifically high in the plasma of AD mice and patients, and miR-206-3p antagomir reversed the Alzheimer phenotype in AD mice.The brain-derived neurotrophic factor (BDNF) gene was negatively regulated by miR-206-3p and upregulated by AEVs-A β+H and miR-206-3p antagomir in AD mice.AEVs-A β+H inhibited δ-secretase (Asparagine endopeptidase, AEP) activation via the miR-206-3p/BDNF axis to alleviate Aβ burden in the AD brain.Conclusion: Our findings highlight the role of aFGF in the modification of AEVs cargoes, especially miR-206-3p that can potentially serve as a biomarker for AD diagnosis and therapeutic target.
Recent advances in understanding the role of HES6 in cancers
Authors: Imène Krossa, Thomas Strub, Arnaud Martel, Sacha Nahon-Esteve, Sandra Lassalle, Paul Hofman, Stéphanie Baillif, Robert Ballotti, Corine Bertolotto
Journal: Theranostics (2022)

The NOTCH signaling system regulates a variety of cellular processes during embryonic development and homeostasis maintenance in different tissues and contexts. Hence, dysregulation of NOTCH signaling is associated with a plethora of human cancers, and there have been multiple efforts to target key components of this pathway. In this review, we briefly highlight the latest research advances in understanding HES6, a poorly studied component of the NOTCH pathway. We summarize the role of HES6 in cancers with a focus on uveal melanoma. Finally, we discuss the ongoing efforts to target the NOTCH-HES6 axis in cancers.
circRNA Mediates Silica-Induced Macrophage Activation Via HECTD1/ZC3H12A-Dependent Ubiquitination: Erratum
Authors: Zewei Zhou, Rong Jiang, Xiyue Yang, Huifang Guo, Shencun Fang, Yingming Zhang, Yusi Cheng, Jing Wang, Honghong Yao, Jie Chao
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.21648.].
Biodegradable electrospun nanofibrous platform integrating antiplatelet therapy-chemotherapy for preventing postoperative tumor recurrence and metastasis
Authors: Jianye Li, Jiaojiao Li, Yuzhu Yao, Tuying Yong, Nana Bie, Zhaohan Wei, Xin Li, Shiyu Li, Jiaqi Qin, Haibo Jia, Qing Du, Xiangliang Yang, Lu Gan
Journal: Theranostics (2022)

The perioperative trauma-related platelet recruitment and activation severely affect tumor recurrence and metastasis. Therefore, efficiently killing residual tumor cells and simultaneously inhibiting platelet activation to block platelet-cancer cell interaction might be a promising strategy to prevent postoperative tumor recurrence and metastasis. Methods: Biodegradable PLGA electrospun nanofibrous films co-delivering doxorubicin-loaded tumor repopulating cell-derived microparticles (DOX-MPs) and aspirin (ASA) were developed as the implant materials (DOX-MPs/ASA@NF) for postoperative in-situ treatment. The characterization, cytotoxicity against tumor cells, inhibition in platelet activation-triggered proliferation, migration and metastasis of tumor cells and in vivo anti-recurrence and anti-metastasis activity induced by DOX-MPs/ASA@NF were systematically evaluated. Results: PLGA nanofibrous films facilitate the enhanced distribution of DOX-MPs as well as DOX-MPs and ASA release in a time-programmed manner within the tumor resection cavity. The released DOX-MPs efficiently kill the residual tumor cells, while ASA decreases platelet activation and inhibits platelet-promoted proliferation, migration and metastasis of tumor cells, resulting in the remarkable inhibition of postoperative tumor recurrence and metastasis. Conclusions: DOX-MPs/ASA@NF may be a promising candidate to prevent the recurrence and metastasis of resectable tumors.